Quetiapine was first described in a patent publication EP 240228 (U.S. Pat. No. 4,879,288). It is prepared starting from dibenzo[b,f][1,4]thiazepin-11-[10H]one of formula II
which is first halogenated with phosphorous oxychloride, then isolated and condensed with 1-(2-hydroxyethoxy) ethyl piperazine to obtain quetiapine. After purification by flash chromatography the yield was 77.7%. As an alternative to halogenation a process via a thioether in the first step is presented.
In the process claimed in EP 282236 the piperazine ring is first condensed with 11-chloro-dibenzo[b,f][1,4]thiazepine and thereafter quetiapine is obtained by its reaction with haloethoxy ethanol. The base is further converted to the hemifumarate salt, which was isolated in 78% yield.
WO 2006/117700 describes a process of EP '228 improved by the destruction of phosphorous oxychloride in situ to decrease the amount of hazardous waste. Phosphorous oxychloride is used only about 1 equivalent to the compound of formula II whereas in the process of EP 240228 it was used in about 15 equivalents.
A reaction of 11-chlorodibenzo[b,f][1,4]thiazepine with a piperazine moiety in the presence of a halide is the improvement described in WO 2006/113425. The process is said to yield quetiapine in high purity.
In WO 2006/094549 there is described a process which avoids the halogenation step and the use of hazardous phosphorous halogenating agents by the reaction of 10H-dibenzo[b,f][1,4]thiazepin-11-one directly with a piperazine derivative. This is achieved by performing the reaction in the presence of titanium alkoxide. Yields of 50-75% as a fumarate salt are reported. Expensive titanium alkoxide is used from about 2 to 3 fold excess to starting compound of formula II.
Also the process of US 2006/0063927 avoids the use of phosphorous compounds in halogenation by using oxalyl chloride as a halogenating agent. The imino chloride is obtained in 66% yield. The reaction of 11-chloro-dibenzo[b,f][1,4]thiazepine with 1-(2-hydroxyethoxy)ethylpiperazine is performed either in the presence of a base in an organic solvent or in a two-phase system. However, the reagent used, oxalyl chloride is poisonous and requires special attention.
A one-pot process for the preparation of quetiapine is described in WO 2007/020011. Phosphorous oxychloride is used in halogenation step about one equivalent to 10H-dibenzo[b,f][1,4]thiazepin-11-one.
WO 2007/004234 describes a process comprising the reaction of chloro ethoxy ethanol with piperazinyl-dibenzo[b,f][1,4]thiazepine dihydrocloride, which is obtained by halogenating the dibenzo[b,f][1,4]thiazepin-11-[10H]one, reacting the imino chloride obtained with piperazine, and treating the obtained compound with an alcoholic solution of hydrogen chloride.
All processes described above use dibenzo[b,f][1,4]thiazepin-11-[10H]one as a starting material. Its preparation requires several steps, and in most cases it has to be even halogenated to the imino chloride before the piperazine moiety can be condensed with it. Halogenating reagents, e.g. phosphorous oxychloride have been used in excess and their removal from the reaction mixture requires evaporation of large amounts.
A different approach using protected intermediates is used e.g. in routes described in WO 2005/014590, WO 2005/028457, WO 2005/028458 and WO 2005/028459. In some cases the reactions may be performed in one pot fashion and no extra purification steps are needed to get a pure product in high yield. However, protection and deprotection steps used lengthen the processes and shorter processes for the preparation of quetiapine are still needed.